X-Chromosome Insight for Targeting Gene Therapy

Inherited retinal dystrophies are a heterogeneous group of genetic vision-threatening diseases primarily affecting the photoreceptor cells. Retinitis pigmentosa (RP) is the most frequent form of inherited retinal dystrophy with a worldwide prevalence of approximately 1 in 4000. The human genetics of RP is extremely complex, and after the first report describing the linkage of an RP locus to a DNA marker on the X-chromosome in 1984, [1] over 150 genes have been associated with either non-syndromic or syndromic forms of RP. A listing can be reviewed at https://sph.uth.edu/retnet/ (accessed on 6 December 2019). RP is usually inherited as autosomal-dominant, autosomal-recessive or X-linked monogenic disease, but digenic and mitochondrial patterns are also described making gene-therapy for RP very challenging. At present, mutations in three genes have been identified as causative of X-linked retinitis pigmentosa (XLRP): retinitis pigmentosa 2 (RP2; OMIM 312600), retinitis pigmentosa GTPase regulator (RPGR or RP3; OMIM 312610), and oral-facial-digital syndrome 1 (OFD1; OMIM300170). In the large majority of XLRP patients the phenotypic manifestations of the disease are severe and ingravescent, portraying one of the most harmful forms of an inherited retinal dystrophy which are often characterized by legal blindness for visual field restriction already starting from the late adolescence or early adulthood. Approximately 70-80% of the total cases of XLRP is caused by mutations of RPGR gene, which encodes a protein involved in the regulation of intra-flagellar proteins trafficking at the level of photoreceptor connecting cilium. It is estimated that the numerous rare variants of the RPGR gene represent one of the most frequent cause of RP overall (about 15% of non-syndromic RP cases), also underlying many cases of atypical inherited retinal dystrophy diagnosed in several heterozygous female carriers belonging to families with a provisional diagnosis of autosomal dominant RP. [2, 3] In this intriguing scenario of multifaceted genotype-phenotype correlations observed in the pedigrees with XLRP, at least three RPGR gene therapy trials are recruiting affected male patients for the completion of their phases 2 or 3 (see https://www.clinicaltrials.gov: ClinicalTrials.gov Identifier NCT03116113, NCT03252847, and NCT03316560, accessed on 6 December 2019), but no explanatory data had been hitherto reported with regard to the female carriers in whom XLRP can manifest with a wide spectrum of possible retinopathies ranging from asymptomatic to severe clinical features similar to those observed in male probands. In this issue of Ophthalmology Retina, Fahim and co-workers [4] finally focus an essential new insight on the role of X-chromosome inactivation (XCI) in determining the phenotypic severity of inherited retinal dystrophy among women with pathogenic RPGR heterozygoses. An extensive knowledge of genotype-phenotype correlations will be required to optimize both candidate identification and treatment timing of gene therapy, quantifying the contribution of genotype, genetic modifiers, and skewing of the XCI ratio from the expected 50:50 ratio to the different retinal phenotypes of each female member of XLRP families. Because of the possibly high penetrance of the retinal pathologic patterns among heterozygotes carriers of RPGR mutations, particular attention is recommended to monitor the likely clinical worsening in the young adults with significant or extreme XCI, who have high risk of XLRP-like disease’s severity for the presence of a lower manifesting-disease threshold in comparison with what has been reported for other X-linked disorders. The recent availability of gene replacement therapy voretigene neparvovec-rzyl, for the treatment of RPE65-related inherited retinal dystrophies has paved the way for anticipated approval of other gene-based therapies such as those utilized in the ongoing clinical trials conducted on XLRP patients with RPGR mutations, whose results are awaited with positive expectations even if they might be counteracted by nonfunctional or detrimental products of RPGR gene. [5] On the other hand, the development of XCI-based models of disease’s expressivity in mutant heterozygous female RPGR carriers can be helpful to rationally plan gene-based interventional strategies by silencing the anomalous gene products. However, in each specific patient-case, a pro-treatment decision-making process will have to be plausibly motivated by indications that the gene therapy is cost-effective compared with standard care using an appropriate spending threshold per quality-adjusted life-year